If you can put aside the emotion of the disease, it offers us a host
of enigmas that are fascinating. It comes across as the most fascinating
tumor, I believe, that one could think of, and there are many reasons
for that.

We can begin with the strange localization of the tumor. It starts on
the skin and in the mucus membranes of the bowel. That is unusual.

We can proceed to say it is unusual in its composition. A lot of blood
vessels proliferating? That is unlike any other tumor. You could say,
“It is a tumor with blood vessels.” Perhaps, and perhaps not.

Another strange feature is that the cellularity of the early tumor is
mixed. It is not the sea of homogeneity that characterizes most cancers,
because it has fibroblasts, white blood cells, and endothelial cells.
All these new blood vessels are all mixed together in what looks more
like a granulomatous reaction or an inflammatory reaction. As you said,
that is giving rise to the notion by some that it is more like an infectious
disease reactivity phenomenon, with cytokine-milieu overplay. I think
much of that is true in the early stages.

We come to another fascinating aspect of Kaposi's sarcoma. Is it cancer
or not? Or is it only what you just said? If it is a real malignancy,
or a true sarcoma–let us get away from the word “cancer” because that implies carcinoma and this is sarcoma–but if it is
a true malignancy, what is the tumor cell? That is also interesting.

It is also peculiar that humans are the only species to get Kaposi's
sarcoma. There are four epidemiologic forms. There is the HIV form; the
African endemic non-HIV form; the transplantation, usually of the kidney,
form; and the so-called classical form in older Mediterranean males, mainly
Greeks, Jews, Spaniards, and Italians. That is who gets it.

Those are all oddities, every one of them. Then why is it in gay men
so much, and why so much in males? Many of these things are strange. Which
one is the most interesting?

Harden: Also, with regard to the latest finding about, perhaps, a pregnancy
hormone that inhibits it?

Gallo: That finding is from our laboratory.

Harden: Let me ask you then to talk about this new finding and what role
it may play in Kaposi's sarcoma?

Gallo: I think that this is an interesting time to talk about Kaposi's
sarcoma, to take a breath, pause, and look at it, because many findings
have emerged in the last few years. I cannot say they have come together.
It is just that there are developments in at least three different areas
that merit really aggressive pursuit. Which one of these will yield the
most fruit, I am not sure, but before we discuss the hormone and this
may be helping to answer part of the question, let us take what I think
are the three areas that are coming together.

First of all, beginning around 1987, we started the first systematic
culturing of the cells of Kaposi's sarcoma, the reasons being: we were
convinced that it was an interesting tumor; we are in the [National] Cancer
Institute; and, it was not being studied by virtually anyone. There was
nothing in the literature about culturing Kaposi's, or almost nothing,
so we set out to culture systematically what we hoped would be the tumor
cell. We spent several years doing that, and I think we now have a summary
of what those results mean, or where we are with them anyway.

Those studies indicated to us that the bulk of the tumor cells, or the
bulk of the cells, I should say, that are proliferating and that can be
grown in the laboratory, are hyperplastic, not cancerous. They are normal
diploid chromosome cells. They are cells involved in responding, I think,
to emergencies, like in wound-healing. They make and respond to many growth
factors. They stimulate angiogenesis. They are probably some kind of primitive
endothelial cell of the blood vessels themselves.

You can also grow–and some laboratories have–fibroblasts
from the tumor called Kaposi's. I now think this is an epiphenomenon.
There are two ways of looking at it. This hyperplasia, this proliferation
or stimulation, that is occurring may be a forerunner of the malignant
cell. This may cause the malignant cell because their growth leads to
an accident in some people, transformation malignancy. But you can look
at it the reverse way too. It may be that the malignant cell is there
in small numbers, like the Reed-Sternberg cell in Hodgkin's disease, and
the malignant cell, which appears for reasons I cannot even dream of yet,
is secreting cytokines that creates the reactive hyperplasia. I am not
sure which is the father and which is the child; the hyperplasia leading
to one of those cells becoming a malignant clone, or the malignant clone
secreting cytokines that create the hyperplasia? That is the problem that
we are stuck with now, but we may have ways to answer that soon. I will
tell you why.

Anyway, if I summarize all that work, it indicated to us: that early
Kaposi's sarcoma involves many different hyperplastic cells; that what
is producing that hyperplasia is ironically the product of chronic immune
activation. AIDS being an immune deficiency is also immune activation.
Some of the cytokines from activated cells are able to activate these
endothelial-like cells, or endothelial-related cells, to grow, proliferate,
and themselves secrete cytokines which produce the blood vessel angiogenesis
and other things as well.

We discovered during that process
that, at least in early Kaposi's sarcoma, a key cytokine that was produced
by these growing spindle cells that are probably endothelial is basic
fibroblast growth factor. Once they have been activated and have proliferated
from activated immune cells, they are making lots of basic fibroblast
growth factor. Basic fibroblast growth factor, we discovered, synergizes
with the tat protein of HIV in promoting blood vessel growth
again and promoting growth of themselves. We published a long article
in Nature about the mechanism of this and so on.

At about this time our laboratory, it was predominantly a visiting scientist
from France, Yanti Lunardi-Iskander, described it. And a laboratory in
Israel, working with classical KS, and us working with HIV KS, have both
succeeded in isolating, from a total of only two patients, malignant cells
for the first time. This data now powerfully argues that Kaposi's does
have malignant cells. But now comes the question: are they there at the
beginning or did they develop later? But now that we have them, we hope
to develop molecular markers and go back and look at all Kaposi's sarcomas
to see if such a cell is there buried within the mess of hyperplastic
cells which we have been studying and which are really an epiphenomenon.
That is where we are right now.

New data that argues for neoplasia
has also come from the epidemiology group at the National Cancer Institute,
[Dr. William] Bill Blattner's branch, involving [Dr. Robert] Bob Biggar,
and from a group at Johns Hopkins, involving a man named [Dr.] Charles
Rabkin, also of NCI. They have shown, in three out of three cases, at
least, that indeed late-stage Kaposi's sarcoma had cells that were clonal,
derived from one papa. If that is true, it is a malignancy. So, this is
now coming together.

During the studies of the malignant
cells, [Dr. Joseph] Joe Bryant, at the Dental Institute [National Institute
of Dental Research], our collaborator, was putting those cells into nude
mice, immune deficient mice, and they developed a big malignancy which
metastasized and killed the animals. We were having a certain amount of
experimental fun with that model when Joe observed that one group of animals
did not get the tumor and he found that those animals were females that
were pregnant. They got pregnant by accident. That is, he housed male
and female infant mice together in the same cages. I never really talked
to him about why he did that. I think it was probably a mistake. But the
pregnant animals did not get the tumor. Then we went after what the factor
was. To make a long story short, we found that it was the serum in the
first trimester of pregnant mice and women, chorionic gonadotrophin, a
hormone of pregnancy that targets the gonads, but God knows what other
functions it might have. We found the bulk of the activity resided in
the beta-chain that was blocking Kaposi's sarcoma cell growth in vitro
and in the mouse. We have learned that it is not blocking growth; it is
killing those cells. So, if you want to make something physiologic of
it, there are two things to think about:

Is there a normal cell that it is killing? What would the normal cell
be? Embryonic, maybe. The first trimester, the molding of the infant,
the hands, for example, maybe there is a cell that is related in lineage
to the cell we call the Kaposi's sarcoma tumor cell? That is a thought.

The other theory it gives rise to, at least in my mind, is that since
the beta-chain was 85 percent homologous to the luteinizing hormone betachain,
and we have shown that luteinizing hormone also has this event, perhaps
that is why women get Kaposi's sarcoma less.

This is now in clinical trials. We will be able to talk about that probably–or
maybe–during the laboratory meeting in late August [1995].

Rodrigues: Dr. Gallo, about a month ago, there was a series of articles
in the popular press about a child who apparently cleared an HIV infection.
I think in the paper they noted that there had been a few other such cases
reported, but this particular one, according to the articles, was very
well documented. I wonder if you are familiar with that case.

Gallo: I am not familiar with it other than by reading about it in the
newspapers like you. I have asked others about it and, if others are accurate
in what they tell me, I do not think that the researchers showed that
the lymphocytes that harbored virus were of the sex of the child. If they
were female, the mother's lymphocytes circulate in babies. That has been
shown long ago. How do the researchers know that they just did not look
at the mother's lymphocytes circulating in the baby, which eventually
get destroyed and that the baby was never infected? That is my answer.

Rodrigues: Around the same time, actually I guess it preceded that somewhat,
there were also reports in the newspapers about the new understanding
of the role of CD8 and T cells in suppressing the HIV infection. We were
curious whether or not you thought that this implied that we understood
more about what was happening in cases of long-term non-progression of
AIDS?

Gallo: No. I do not think we have any notion whatsoever why some people
progress less rapidly. Maybe it is HHV-6. I am sure that is something
that has not even been looked at. Not that I predict it is, but I do not
think it has been looked at properly. One person may have better control
of HHV-6 and it may not be replicating as much. That is an interesting
idea. Some researchers cannot distinguish what is the cart and what is
the horse. They look at the lymph nodes and they are worse in the person
who is doing poorly than in the person doing better. What would you expect?
So, is the lymph node not being in good shape the cause of progression
or, if it is in good shape, the cause of non-progression, or is that just
symptomatic of the fact that a person has much more virus when AIDS is
progressing and destroying the lymph node, or the immune system is destroying
it? The real problem is to try to prove what is cause and what is effect,
and nobody has done that yet.

Regarding CD8, I do not know of any new data that says it is important.
There has been a factor that suppresses HIV replication that was described
by [Dr. Jay] Levy back around 1986-87. The horrible frustration is that
there has never been a report of the identification of the factor or its
gene cloning or any publication on what it is; only what it is not. In
fact, that has led, in the last year, out of frustration, one wanted to
have the time to do something with it, to others getting involved in the
problem, including our own laboratory, and we know that there are at least
two such factors. There are at least a few factors secreted by CD8 cells
which are anti-HIV replication. CD8 cells can also be, as you know, cytotoxic
killer cells and can kill by mechanisms that involve the so-called “kiss
of death.” There are many ways in which CD8 cells may be important.
There is no doubt CD8 cells are important in immunology, therefore you
can conclude that they are important in AIDS. But whether they are what
is responsible for the difference in survival between one group and another
group is a question. I am sure they are helpful to both groups, but whether
I am marked, if I am not doing well because my CD8 cells have some predetermined
way of fading out earlier than yours, who does not go as fast, is far
from clear. There is no evidence for that that I know of.

Rodrigues: Apparently it is rather difficult to design experiments that
can look at that?

Gallo: Yes. I guess it is. I think so.

Harden: Let us move a little away from specific questions and see if
you will give us an overview on the current prospects for developing a
successful vaccine against AIDS?

Gallo: I believe that the development of a preventive vaccine is totally
unpredictable. I do not see anybody being in a position to say whether
we should, or should not, go forward with trials of anything. As you know,
I do not like to be diplomatic very much, but I can be sympathetic with
the argument this way, and I can be sympathetic with the argument that
way. In other words, if you argued one way, I would argue the other. If
you would say, “We should go forward with trials,” I would argue
that it is crazy, because you will cause reactions in the field, [and]
lack of faith in the science, and you will make it impossible to go forward
in the future. You will mark those people with an immune response and
it will be hard to tell in the future what is happening with them. They
will not be available for other trials. We do not have proof these vaccines
are really ready. You might even produce enhancing antibodies that facilitate
infection. There are many negatives.